Studies of the mechanisms of genetic control of recovery of adult mice from Friend virus complex (FV)-induced leukemia revealed that the H-2D subregion appeared to influence recovery by altering the kinetics of generation of FV-specific helper T lymphocytes. In addition, gene(s) within the H-2 complex were found to affect the ability of FV to induce immunosuppression to non-retroviral antigens. This resistance to retrovirus-induced immunosuppression occurred in the presence of viremia and persistent leukemic splenomegaly. Furthermore, immunosuppression was not inhibited by the presence of the Rfv-3r/s genotype which enabled certain leukemic mice to mount an effective humoral immune response to FV. Mice with the H-2a/a and Rfv-3r/s genotypes appeared to be similar to AIDS patients in that they made humoral antiviral antibody but were immunosuppressed to challenge with nonviral antigens. Thus, the immune response to viral and nonviral antigens appeared to be influenced by separate host genes in this system. Elucidation of the factors controlling these immune responses should be of value in understanding similar responses in AIDS.